Several aspects of regulation of phospholipase C-coupled receptors have been studied in cerebellar granule cells. We have shown that 7-day, but not 1-day, treatment of cerebellar granule cells in culture produced an up-regulation of quisqualate receptor-mediated phosphoinositide (PI) turnover due to persistent activation of GABA(A) receptors. Moreover, 7-day GABA treatment also produced a GABA-dependent inhibition of excitatory amino acid- and KC1 (25 mill)-induced PI hydrolysis. Thus, GABA-treated cells have developed a dependence on GABA to suppress excitatory amino acid-induced PI hydrolysis. A rapid abstinence syndrome occurred upon GABA withdrawal. Tolerance to GABA did not readily occur during treatment. In another study, sodium nitroprusside was found to be neurotoxic to cerebellar granule cells. This neurotoxic effect appeared to be due to lowering of intracellular calcium [Ca 2+ )i and wall independent of its ability to stimulate cGMP production. Stimulation of cells with glutamate results in rapid translocation and down-regulation of protein kinase C isozymes types II and III. Only the type II isozyme was translocated to a detergent-nonextractable membrane fraction. This translocation and down-regulation of protein kinase C may underlie the neurotropic and neurotoxic effects of glutamate. A cross-talk between receptor second messenger systems was also observed in granule cells. Stimulation of adenosine A2 receptors resulted in marked inhibition of PI response to histamine and 5-HT Mediated by histamine H1 and 5-HT 2 receptors, respectively. cAMP-increasing agents partially mimicked the adenosine effect. Moreover, prestimulation of granule cells with carbachol resulted in homologous desensitization which was associated with a loss of muscarinic receptor sites and down-regulation of m2- and m3-receptor mRNA. The mRNA down-regulation was blocked by muscarinic antagonists which alone produced significant up-regulation of muscarinic receptor mRNA.